Summary MS is a chronic inflammatory disease of the central nervous system (CNS), characterized by myelin loss, varyingdegreesofaxonaldamage,andprogressiveneurologicaldysfunction.Itisthemostcommondisabling neurologic disease of young adults and adolescents, affecting 2.3 million individuals worldwide. Despite a large number of disease modifying therapies (DMT) that have shown great promise in the clinical setting, a recentmeta?analysisofstandardizedmortalityratiosinNorthernEuropeanandCanadiancohortsconcluded that the ~two?fold excess mortality in people with MS relative to the general population has remained unchanged for decades. It is hoped that longer usage of more modern DMTs will improve those values over time,andthatmoremoderngeneticstudiesofMSwillpointtonewspecifictargetsforintervention.However, todoso,researchersmustclearlydelineatethegenesinvolvedinpathologyandinterprettheiractioninaway thatisuseful.ThestudyofMSgenesisstillinearlystages.Thebroad,long?termobjectiveofourhighrisk/high gain proposal is to enhance knowledge of the genetic control of autoimmunity and demyelination in the human disease, multiple sclerosis (MS). We use animal models tested for EAE (experimental allergic encephalitis) to dissect genetic pathways that contribute to pathogenesis and understand mechanisms that mightbegoodtargetsfornewtherapies. While we know quite a bit about autoimmunity in this disease, MS is still incurable. We believe that more emphasis in translating ?natural? resistance to demyelinating disease, such as that observed in inbred mouse strains, will be useful. For example, it could be efficacious to stimulate specific regulatory T cells in an MS patientthathasadeficitofthem.Wehavediscoveredoneinbredconsomicmousestrainthatshowsextreme, non?sex?specific EAE?resistance that may naturally use this way of resisting disease. The only genetic information conveying EAE?resistance from the parental strain (PWD) to the background strain (B6) is on chromosome10.Thisintervalhasnowbeenreducedtoasmallenoughregiontoconductpositionalcloning forgeneidentification.WhatisinterestingabouttheseconsomicmiceisthattheirEAE?resistancesegregates withlowerexpressionofIL?17andTimp3,andwithhighernumbersofFoxP3+regulatoryTcells,possiblydue to their characteristically poor APC function. That these mice do this naturally indicates the possibility of translating their EAE?resistance pathway for the benefit of MS patients. Our goals are to select EAE?resistant micefromthosebearingincreasinglyreducedintervals;tocomparegeneexpressionintheircellscomparedto susceptibleB6miceunderconditionsofstimulationinvitro;andtotestifoneoftheexcellentcandidategenes inthereducedintervalisnecessaryfortheirEAEresistanceusingknockoutmice.Insodoing,weproposeto findageneandpathwaythatishomologoustoanMS?gene/pathwaythatistargetablefornovelMStherapies.